Induction of nitric oxide synthase activity in phagocytic cells inhibited by tricyclodecan‐9‐yl‐xanthogenate (D609)

Abstract

1 The synthesis of nitric oxide (NO) by immune-stimulated murine phagocytic cells (J774) and the modulation of this synthesis by tricyclodecan-9-yl-xanthogenate (D609), a specific inhibitor of phosphatidylcholine-specific phospholipase C (PC-PLC), was investigated. D609 dose-dependently suppressed production of NO, as measured by the release of nitrite and nitrate, in response to lipopolysaccharide (LPS) and interferon-y (IFN-y) in intact cultured cells with an ICm of approximately 20 ltg ml"-'. D609 at 40 pg ml ' completely abrogated immune-stimulated nitrite production. 2 The inhibitory effects of D609 on nitrite production were time-dependent and restricted to the first 18 h post-stimulation. D609 did not inhibit nitrite production in the cytosol of immune-stimulated phagocytes. 3 These findings indicate that the xanthogenate, D609, is a potent inhibitor of the induction of NO-synthase activity in immune-stimulated phagocytes. Furthermore, since D609 has been demonstrated to inhibit PC-PLC specifically, our findings suggest that the activation of this enzyme by LPS and IFN-y is a proximal step in the signal transduction of inducible NO-synthase in phagocytic cells.

Prevention of experimental allergic encephalomyelitis by targeting nitric oxide and peroxynitrite: Implications for the treatment of multiple sclerosis

“…Administration was continued daily until at least 2 days after all untreated PLP-immunized mice became severely paralyzed. Tricyclodecan-9-yl-xanthogenate (D609) inhibits iNOS induction by blocking the activity of phosphatidylcholine-specific phospholipase C, a key enzyme in the signal transduction pathway leading to iNOS activation (23). Mice were given 1 mg of D609 (Biomol, Plymouth Meeting, PA), a dose which was selected as one-half the amount suspected to have toxicity based on in vitro experiments.…”

Prothrombin Kringle-2 Activates Cultured Rat Brain Microglia

“…The PLC pathway plays an important role in iNOS expression in macrophages (26,27). Therefore, we examined whether PLC was involved in the prothrombin-and kringle-2-induced NO release from microglia by using the PLC inhibitors D609 (D), a phosphatidylcholine-PLC-specific inhibitor, and U-73122 (U), an inhibitor of PLC␤ and ␥.…”

Inhibition of Experimental Melanin Protein-induced Uveitis (EMIU) by Targeting Nitric Oxide via Phosphatidylcholine-specific Phospholipase C

“…IFN-, one of the Th1 cytokines, is a prominent cytokine in EMIU [36]. D609 inhibits the induction of iNOS in response to IFN- [12], resulting in inhibition of EMIU.…”

“…Tricyclodecan-9-yl-xanthogenate (D609) is a specific inhibitor of phosphatidylcholine-specific phospholipase C (PC-PLC), a key enzyme in the signal transduction pathway leading to iNOS activation and in the regulation of the promoter, nuclear factor-kappa B (NF-B) [12][13][14]. Therefore, D609 suppresses the induction of iNOS activation as well as TNF-induced apoptosis.…”